Dr. Jean Wang is an Instructor of Medicine in the Division of Gastroenterology at the Johns Hopkins University School of Medicine and a Ph.D. student in the Graduate Training Program in Clinical Investigation, a joint program sponsored by the Johns Hopkins Schools of Public Health and Medicine. Her immediate career goals are to complete and publish her Ph.D. thesis work in Clinical Investigation and to establish a career in clinical investigation. Dr. Wang's long-term career goals are to become an independent clinical investigator in gastrointestinal oncology with expertise in patient-oriented research involving genetic epidemiology, outcomes, and prevention. This award will enable her to acquire the skills to become a leader in clinical investigation under the guidance of her mentors and through additional coursework in genetic epidemiology, bioinformatics, and clinical research study design. Patients with Barrett's esophagus (BE) have an increased risk of esophageal adenocarcinoma that is 40-125 times higher than in the general population. However, there are currently no reliable predictors of neoplastic progression. DMA hypermethylation is an epigenetic phenomenon that holds great promise as a molecular marker for early detection of cancer. We hypothesize that DNA hypermethylation will predict which patients with BE are likely to progress to adenocarcinoma. We propose the following specific aims utilizing a panel of 8 cancer-related genes (p16, E-cadherin, APC, ER, MGMT, DARK, RAR-beta and TIMP3): 1) To compare the prevalence of gene hypermethylation in BE patients with different grades of dysplasia and/or adenocarcinoma;2) To determine whether the presence of gene hypermethylation in initial biopsies of BE patients is associated with progression to adenocarcinoma, and to compare gene hypermethylation with currently available markers for neoplastic progression;and 3) To determine whether methylated DNA from BE and/or adenocarcinoma can be detected in the peripheral blood of patients, by comparing methylation profiles of esophageal biopsy specimens with peripheral blood samples taken at the same time. Using these specific aims, we will compare the utility of DNA hypermethylation with current markers for neoplastic progression (detection of dysplasia and p53 immunohistochemical staining). Our long-term goal is to determine whether DNA hypermethylation can identify BE patients who are at high risk for neoplastic progression, thus allowing for early intervention and preventive measures. This research is of significant relevance to public health because the incidence of esophageal adenocarcinoma in the U.S. has increased more than 300% in the past 40 years and BE is considered to be the primary risk factor for esophageal adenocarcinoma.